Human bronchus, pancreatic duct and esophagus can be cultured for several weeks in a chemically defined medium. This controlled experimental setting provides an excellent in vitro system to study the metabolism of chemical carcinogens, including those found in tobacco smoke and the environment. Several classes of chemical carcinogens, polynuclear aromatic hydrocarbons, N-nitrosamines, hydrazines, and mycotoxins, can be metabolically activated by human tissues. The metabolic pathways leading to the formation of DNA adducts in cultured bronchus and esophagus have been defined for benzo(a)pyrene, aflatoxin B1, and N-nitrosodimethylamine. The pathways to organic-extractable and water-soluble metabolites of benzo(a)pyrene were qualitatively similar in all 3 tissues. The adducts between these carcinogens and DNA in human bronchus and esophagus are essentially the same as those found in experimental animals in which the chemicals are carcinogenic. When different people are compared a marked variation in binding levels is found e.g., the interindividual variation in the binding of BP to DNA in cultured human bronchus was 75-fold (100 patients). A variation in carcinogen binding levels in different target tissues within an individual was also found.